Triple-negative breast cancer (TNBC), which accounts for 15-20% of breast cancers, causes the highest mortality rate among all breast cancer subtypes. Due to its heterogeneity and lack of estrogen and progesterone receptor or human epidermal growth factor receptor 2 expression, valuable targeted therapy is limited. Therefore, it is critical to identify novel therapeutic targets in TNBC. 2-oxoglutarate (2-OG)-dependent enzymes, including prolyl hydroxylases (EglN1-3), histone demethylases (for example, KDM5A) and DNA hydroxylases (such as TET1-3), are associated with cancer progression. However, the role of these enzymes in TNBC has never been systematically studied. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth, while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3 mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1 mediated glycolysis, which leads to apoptosis and impaired cell cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacological inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting previously uncharacterized BBOX1-IP3R3-calcium oncogenic signaling axis in TNBC.

Citation Format: Chengheng Liao, Yang Zhang, Cheng Fan, Laura E. Herring, Juan Liu, Jason W. Locasale, Mamoru Takada, Jin Zhou, Giada Zurlo, Lianxin Hu, Jeremy M. Simon, Travis S. Ptacek, Victor G. Andrianov, Einars Loza, Yan Peng, Huanghe Yang, Charles M. Perou, Qing Zhang. Identification of BBOX1 as a therapeutic target in triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-10.